Ординатура / Офтальмология / Английские материалы / Mastering Corneal Collagen Cross-linking Techniques (C3-R CCL CxL)_Garg, Kanellopoulos, O'Brart, Lovisolo, Pinelli_2008

INTRODUCTION

In last one decade Corneal Refractive Surgery has advanced rapidly with excellent visual results worldwide. Refractive surgeons have come across the problem of Post Refractive Keratectasia or Corneal ectasia. Due to effect of Excimer Laser photoablation on the corneal biomechanical properties a significant decrease in the bio mechanical assets was found after surgery. This implies that due to creation of flap and subsequent corneal thinning by ablation weakens the cornea and decreases its elastic properties. This leads later to corneal ectasia. This is indicator for the clinical significance of evaluating corneal biomechanical properties specifically the corneal hysteresis and resistance factor in screening refractive surgery patients. Similarly in Keratoconus (a progressive non inflammatory cone like Ectasia) the corneal hysteresis (CH) and corneal resistance factor (CRF) are significantly lower than in the normal eyes and post Lasik surgery corneas Low values of CH means that the cornea is less capable of absorbing the energy of the air pulse whereas low values of CRF indicates that corneal rigidity is lower than normal. The corneal biomechanical properties are primarily determined by the collagen fibres and the degree of interfibrillar linkage. Corneal Ectatic conditions whether inflammatory or non inflammatory have weak interfibrillar linkage strength.

WHAT IS CROSS-LINKING?

Cross-linking of human Collagen is a physiologic process. Corneal Collagen Cross-linking also known as C3-R/CCL/CxL treatment is a new approach to increase the mechanical and chemical stability of corneal tissue. The primary aim of this treatment is to create additional chemical bonds inside the corneal stroma by means of a highly localized photopolymerization while minimizing exposure to the surrounding structure of the eye. This procedure was first developed by Prof. Theo Seiler, Prof. Wollensak and Prof. Eberhard Spoerl in 1998 at the University of Dresdan, Germany. They did this procedure in cases of progressive Keratoconus and Post Refractive Corneal Ectasia. Followed this other studies undertaken by Dr A Caporossi, Dr Roberto Pinelli and their colleagues

2 (Italy) and Dr Brian Boxer in USA.

There are several different techniques of crosslinking. The most promising technique in cornea is use of UV light and Riboflavin (Vitamin B2 solution) for inducing cross-linking to increase biomedical rigidity of the cornea. This slows down or even stops the progressive thinning of the cornea. In this Photopolymerisation is performed by means of a nontoxic and soluble photo mediator (Riboflavin) and a wavelength which was absorbed strongly enough to protect deeply layers of the eye. (Riboflavin - UVA technique).

PHYSIOLOGY OF COLLAGEN CORNEAL CROSS-LINKING

In this procedure custom made Riboflavin eye drops are applied to the cornea which is then activated by ultraviolet light. Using UVA at 370 nm, the photosenstizer Riboflavin is excited into its triplet state generating reactive oxygen species (ROS) which is mainly singlet oxygen and to a much less degree superoxide anion radicals. The ROS can react further with various molecules including chemical covalent bonds bridging amino groups collagen fibrils / type II photochemical reaction (Fig. 1.1 and 1.2). The wavelength of 370 mm of UVA is chosen because of an absorption peak of Riboflavin at this wavelength Biomechanical studies have shown an increase in the corneal rigidity of 328.9% in human cornea after crosslinking (Fig. 1.3). The increase on biomechanical rigidity after C3-R is probably caused by an increase

Figure 1.1: Bonding tissues and cross-linking

Figure 1.2: Strengthening of corneal fibres by C3-R Treatment

Figure 1.3: UV-XTM Illumination system

in the collagen fiber diameter due to interfibrillar and Intrafibrillar covalent bonds by photosensitized oxidation cross-linking. The cross-linking results in more compact stronger corneas that are more resistant to biomechanical deformation or ectasia.

INDICATIONS FOR C3-R TREATMENT

•Progressive keratoconus

•Iatrogenic post refractive keratectasia (Post Lasik Ectasia)

•Pellucid marginal degeneration.

EXCLUSION CRITERIA

•Corneal thinkness less than 400 um at thinnest position

•Keratometric readings above 60 Diopter

•Active ocular disease

•Herpes Keratitis

•Diabetes

•Pregnancy

•Previous ocular surgery other than Laser refractive surgery

•Immunocompromised Patients

•Patients with known sensitivity.

PARAMETERS FOR C3-R TREATMENT

•Disorder should be progressive in nature

•Thinnest corneal pachymetry higher than 400 um

•No central corneal scarring

•Maximum corneal curvature should not exceed 60 D.

PREOPERATIVE WORK UP FOR C3-R TREATMENT

•Visual acuity assessment (UCVA, BCVA, Contrast senstivitiy)

•Intra ocular pressure recording

•Detailed Slit Lamp Examination specially for Vogts Striae, Fleischer’s ring and corneal scarring

•Slit lamp photographs of corneal changes

•Pentacam evaluation for central corneal thickness and thinnest pachymetry

•Corneal Topography

•OCT Examination.

STEPS OF C3-R TECHNIQUE (FIG. 1.4)

The procedure takes place ambulatory and takes about one hour.

•First eye is anesthelized with Topical proparacaine 0.5 eye drops. Then Manual debridement of corneal epithelium. (Thin surface layer) is abrased in the

central 7 mm of cornea in order to allow penetration of stroma. Riboflavin solution containing 0.1% Riboflavin, 20% Dextran T 500 in isotonic sodium chloride solution (ph 7.0) is applied every 3 minute for the first 30 minutes. This is followed by irradiation of cornea with 365 nm UVA using UV-XTM for 30 minutes. Riboflavin drops are then continued for another 30 minutes at the interval of every 5 minutes as the eye is exposed to a UVA light positioned above the cornea to deliver predetermined dose of UVA light. The distance between the UV delivery system and cornea should be 5 cm (50 mm) so as to deliver a dose of 3 mw/cm2 (Total of 5.4 J/cm2 in 30 mts). As the UVA light interacts with the Riboflavin chemical bonds (cross links) form between the Corneal Collagen molecules and make the Cornea stiffer. As a result the corneal collagen tissue is stronger and can more uniformly retains its natured curved shape rather than bow forward into the cone like shape that is hallmark of Keratoconus and corneal ectasia.

At the end of treatment the cornea is flushed with BSS and a bandage contact lens is placed over the cornea.

POSTOPERATIVE FOLLOW-UP

Patient is prescribed Topical antibiotics, nonsteroidal anti inflammatory and Lubricating eye drops in the postoperative period. Eye may be little painful after the treatment and it may take off after 48 hours. Till the closure of epithelial defect the patient is followed

up everyday. Bandage contact lens is taken off when epithelial defect heals. Subsequent follow-up should be taken at 1 week, 4 weeks, 12 weeks, 24 weeks and 1 year. On each follow-up Refraction, Keratometry, Slit lamp and Pentacam Examination is mandatory. OCT is done at the one month visit and subsequent visits.

FUTURE PROSPECTS

Corneal Collagen Cross-linking with Riboflavin and UVA for the treatment of progressive keratoconus and post refractive keratectasia are relatively safe and effective treatment. The ability to permanently strengthen the inherently weakned cornea is a major advancement and achievement of this technique. C3-R treatment alone or combined with intacs implantation in Keratoconus are allowing improved vision and comfort to the patients. C3-R is a simple, safe and effective procedure in the management of progressive ectatic disorders of the cornea. C3-R treatment shall become a standard treatment in near future.

A lot of clinical research works is going on for the further improvement and wider applications of this treatment, New Clinical research works have started for possible combining of C3-R treatment with topography guided advanced surface ablation, intacs, orthokeratology and conductive keratoplasty. Possible C3-R treatment applications in treating corneal edema, bullous Keratopathy are also being investigated with lot of hope and promise.